Diphenylmethylene spiranes

ABSTRACT

DIARYLMETHYLENE SPIRANES, PROCESSES FOR THE PREPARATION OF THE SAME AND INTERMEDIATES PRODUCED BY SAID PROCESSES. THE COMPOUNDS HAVE UTILITY AS ANTIFERTILITY AGENTS, LIPID NORMALIZING AGENTS, CENTRAL NERVOUS SYSTEM AGENTS, ESTROGENS AND ESTROGEN ANTAGONISTS.

United States Patent 3,636,166 DIPHENYLMETHYLENE SPIRANES Daniel Lednicer, Portage, Mich., assignor to The Upjohn Company, Kalamazoo, Mich. No Drawing. Filed Mar. 10, 1969, Ser. No. 815,512 Int. Cl. C07c 39/08, 39/12 US. Cl. 260-619 A 1 Claim ABSTRACT OF THE DISCLOSURE Diarylmethylene spiranes, processes for the preparation of the same and intermediates produced by said processes. The compounds have utility as antifertility agents, lipid normalizing agents, central nervous system agents, estrogens and estrogen antagonists.

BRIEF SUMMARY OF THE INVENTION This invention relates to novel diarylmethylene spiranes, processes for preparing the same and novel intermediates prepared by said processes. The novel diarylmethylene spiranes of this invention have the formulae:

a we) (CH2 n R (III) wherein R and R individually are similar or different alkyl groups of from 1 to 4 carbon atoms, inclusive, and when taken together with the attached nitrogen atom form the residue of a saturated heterocyclic amine of 5 to 7 ring members, inclusive; m is an integer from 2 to 6, inclusive, and n is an integer from 4 to 6, inclusive, provided that when R of Formula I compounds is hydrogen or alkyl, R is other than hydrogen or alkyl.

Examples of halogen are fluorine, chlorine, bromine, and iodine. Examples of alkyl of from 1 to 4 carbon atoms, inclusive, are methyl, ethyl, propyl, butyl and isomeric forms thereof. Examples of alkoxy of from 1 to 4 carbon atoms, inclusive, are methoxy, ethoxy, propoxy, butoxy and isomeric forms thereof. Examples of alkanoyloxy of from 1 to 4 carbon atoms, inclusive, are formyloxy, acetoxy, propionyloxy, butyryloxy and isobutyryloxy.

The term dihydroxyalkoxy of from 2 to 5 carbon atoms, inclusive is inclusive of l,2-dihydroxyethoxy, 2,3- dihydroxypropoxy, 2,3-dihydroxybutoxy, and the like. The term residue ofa saturated heterocyclic amine of 5 to 7 ring members, inclusive is inclusive of pyrrolidino-, alkylpyrrolidino such as 2-methylpyrrolidino-, 2,2-dimethylpyrrolidino-, 3-methylpyrrolidino and the like; piperazino, alkylpiperazino such as Z-methylpiperazino, 4- methylpiperazino-, 2,4-dimethylpiperazino, and the like; piperidino, alkylpiperidino such as 2-methylpiperidino, 3-methylpiperidino, 4,4-dimethylpiperidino, and the like; morpholino, hexamethylenimino, homopiperazino, and the like.

The term novel compounds of this invention as used throughout the specification embraces the compounds represented by the Formulae I, II, and III above, including the acid addition salts and quaternary ammonium salts of said compounds that contain tertiary amino groups, and the alkali metal and alkaline earth metal salts of the compounds of Formulae I, II, and III wherein either R or R or both represent hydroxy.

The processes for making the novel compounds of Formulae I and II wherein both R and R, are alkoxy, substituted alkoxy (for example, dihydroxyalkoxy, tertiary aminoalkoxy) or alkanoyloxy are illustrated in the following equations wherein Ra is selected from the group consisting of (a) alkyl of from 1 to 4 carbon atoms, inclusive, (b) dihydroxyalkyl containing from 2 to 5 carbon atoms, inclusive,

a wherein R R and m are the same as above and (d) alkanoyl of from 1 to 4 carbon atoms, inclusive; and n is the same as above.

In step 1 of both reaction schemes A and B, the esters (V and VI) are reacted with the Grignard reagent from the tetrahydropyranyl ether of p-bromophenol followed by acid hydrolysis, to form I and II' which are then etherified or acylated to form the ether or acylated compounds represented by Formulae Ia and IIa.

In preparing compounds of Formulae I and II wherein R and R are the same and other than substituted alkoxy or alkanoyloxy only step 1 is used. In these instances the appropriate Grignard reagents are used.

The processes utilized for preparing the compounds of Formula I wherein R and R are different or the compounds of Formula III, are illustrated by the following equations:

(@Ocu (@0 Gal 6 VIE VIII wherein R, R and n are the same as above.

In step I of both reaction schemes 'C and D, a nitrile (VII) is reacted with the appropriate Grignard reagent to form a ketone (VIII) and the resulting ketone is reacted with a diiferent Grignard reagent to form the desired diarylmethylene spirane lb, or with butyl lithium and 4-bromopyridine to form an intermediate tertiary carbinol which is dehydrated to form the desired diarylmethylene spirane III.

Compounds of Formula II wherein R and R are different (i.e., compounds of Formula IIb) can be prepared in a similar manner, that is, in a manner similar to process C above.

DETAILED DESCRIPTION The spiro esters (V and VI) and the spiro nitriles (VII) utilized as starting materials are prepared by a procedure illustrated by the following equations:

wherein X is earbalkoxy or cyano, and n is the same as above. In step (a) the aldehyde (IX) is reacted with pyrrolidine to form the enamine (X). In step (b), the enamine is reacted with an alkyl acrylate or acrylonitrile to form (XI). In step (c), XI is reacted with methyl iodide and then base to form XII, which is reduced (step d) to form XIII. The conditions and other parameters of this procedure are discussed in detail by Christol et al., Bull. Soc. Chirn. France, 3947 (1967). The aldehydes utilized in procedure E are readily available from commercial sources or they may be prepared by methods well known in the art.

The compounds of Formulae I and II where both R and R are alkoxy, substituted alkoxy or alkanoyloxy are prepared in accordance with reaction schemes A and B set forth above.

In step 1, the ester (V or VI) is reacted with the Grignard reagent formed from the tetrahydropyranyl ether of p-bromophenol in the presence of an inert solvent, such as tetrahydrofuran. After the addition of two molecules of the Grignard agent has occurred, the crude product is hydrolysed in aqueous acid to remove the protecting group. The intermediate tertiary carbinol that is formed rapidly dehydrates to yield the desired product (I' or II). The mole ratio of Grignard reagent to ester is preferably 2 to 1, however, higher or lower ratios may be used. The addition reaction proceeds readily at 25 C., however, higher or lower temperatures may be used if desired. In addition to tetrahydrofuran, other solvents that may be used include diisopropyl ether, and mixtures of tetrahydrofuran and benzene.

In step 2, the phenols (I and II) are alkylated or acylated to form the others and acylated compounds of Formulae Ia and 11a. Both the alkylation and acylation are readily accomplished by methods well known in the art.

Illustratively, the compounds of Formulae Ia and 11a wherein Ra is tertiary aminoalkyl or alkyl can be prepared by treating the compounds of Formulae I or II with the appropriate tertiaryaminoalkyl halide or alkyl halide in the presence of a base such as sodium hydroxide, sodium methoxide and the like. The etherification is conducted advantageously in the presence of an inert organic solvent such as tetrahydrofuran, dioxane, or a lower alkanol, e.g., methanol, ethanol and isopropanol.

Similarly, the compounds of Formulae Ia and Her wherein Ra is dihydroxyalkyl can be prepared by alkylating the compounds of Formulas I and II with the appropriate dihydroxyalkyl halide in the presence of a base such as sodium hydroxide, sodium methoxide, and the like. The alkylation is conducted advantageously in the presence of an inert organic solvent such as tetrahydrofuran, dioxane, a lower alkanol, e.g., methanol, ethanol, isopropanol and the like.

The compounds of Ia and Ila wherein Ra is acetoxy, are prepared by heating a solution of the phenol I or II and acetic anhydride and then removing the excess reagent by distillation under a high vacuum. Similarly, compounds wherein Ra is formyloxy, propionyloxy, butyrylo-Xy or isobutyryloxy can be prepared by replacing acetic anhydride with formic acetic anhydride, propionic anhydride, butyric anhydride or isobutyric anhydride, respectively.

Compounds of Formulae I and II wherein R and R are different and compounds of Formula III are prepared according to the processes illustrated in reaction schemes C and D, respectively.

In step 1 of these processes, the nitrile (VII) is reacted with one equivalent of the appropriate Grignard reagent in the presence of tetrahydrofuran or other and then the reaction mixture is worked up under neutral conditions to yield an intermediate imine. This reaction is conducted at temperaures of 0-65 C. The imine is then hydrolysed, by treating it with aqueous hydrochloric acid, to give the ketone (VIII).

In step 2, the ketone (VIII) is reacted with the appropriate Grignard reagent in the case of process C, or with butyl lithium and 4-bromopyridine in the case of process D. The crude product is then worked up to afford the final product (Ib, IIb or III). In this reaction carbinols having the formulae:

i@ yl E n s m xv wherein R, R and n are the same as above, are formed. Some of the carbinols dehydrate during the reaction and therefore compounds Ib, IIb, and III are obtained without the use of an additional dehydration step. With other of the carbinols, dehydration will occur only through the use of special procedures. For example, the carbinol may be heated alone of the presence of various materials, e.g., potassium acid sulfate or it may be refluxed in benzene in the presence of p-toluenesulfonic acid. Details of this type of dehydration along with various other materials that may be utilized to facilitate it are described in US. Pat. No. 3,287,397.

The acid addition salts of the invention comprise the salts of the basic compounds of Formulae I, II and III above with pharmacologically acceptable acids such as sulfuric, hydrochloric, nitric, phosphoric, lactic, benzoic, methanesulfonic, p-toluenesulfonic, salicylic, acetic, prOpiOnic, maleic, malic, tartaric, citric, cyclohexanesulfamic, succinic, nicotinic, ascorbic acids, and the like.

The quaternary ammonium salts of the invention are the salts obtained by reaction of the tertiary amino compounds of Formulas I, II and III with quaternating agents, for eX- ample alkyl halides, alkenyl halides, dialkyl sulfates, aralkyl halides, alkyl arylsulfonates, and the like. The term alkyl means alkyl of from 1 to 4 carbon atoms, inelusive. The term alkenyl means alkenyl of from 3 to 8 carbon atoms, inclusive, such as allyl, 2-butenyl,, 2-pentenyl, Z-hexenyl, 2heptenyl, 2-octenyl, and isomeric forms thereof. The term aralkyl means an aralkyl group containing from 7 to 13 carbon atoms, inclusive, such as benzyl, phenethyl, 2-phenylpropyl, benzhydryl and the like. The term alkyl arylsulfonates means the esters formed from alkanols and arylsulfonic acids such as benzenesulfonic, toluenesulfonic, xylenesulfonic, and the like acids. Examples of quaternary salts of the compounds of the invention are the methobromide, methiodide, ethobromide, propyl chloride, butyl bromide, octyl bromide, methyl methosulfate, ethyl ethosulfate, allyl chloride, allyl bromide, benzyl bromide, benzhydryl chloride, methyl toluenesulfonate, ethyl toluenesulfonate and the like.

The compounds of the invention exhibit pharmacological activity in animals, including mammals. For example, they are useful in the treatment of hyperlipemic states in animals. Illustratively, the compounds 4,4-(spiro 3 .5 non-2-ylidenemethylene)diphenol,

a- [p- 2- l-pyrrolidinyl) ethoxy] phenyl] -a-spiro 3 .5] non- 2-ylidene-p-cresol,

4,4'- (spiro [3 .5] non-2-ylidenemethylene) diphenol diacetate,

a- [p- (dimethylamino phenyl] x-spiro [3 .5] non-Z-ylidenep-cresol,

u- (p-methoxyphenyl) -a-spiro [3 .5]non-2-ylidene-p-cresol,

4,4- [spiro [cyclobutane-l ,2-norbornan] -3-ylidenemethylene] diphenol hemihydrate,

4,4-(spiro [3.4] Qct-Z-ylidenemethylene)diphenol,

1, l'- [spiro [3.5] non-Z-ylidenemethylenebis (p-phenyleneoxyethylene) dipyrrolidine dihydrochloride and poc-SpiI'O [3 .5] non-2-ylstyryl) anisole lower serum chloesterol and triglyceride levels when administered orally to rats in dosages of 1 mg./kg. to mg./ kg.

The compounds of Formulae I, II and III also exhibit antifertility activity. For example 4,4- (spiro [3 .5 nOn-Z-ylidenemethylene) di phenol,

1, l- [spiro [3 .5] non-2-ylidenemethylenebis (p-phenyleneoxyethylene) ]dipyrrolidine dihydrochloride,

4,4- (spiro 3 .5] non-2-ylidenemethylene diphenol diacetate,

4,4'- (spiro[ 3 .4] oct-2-ylidenemethylene) diphenol,

4,4- (spiro [3 .4] oct-2-ylidenemethylene diphenol diacetate and 1, 1 (spiro [3 .4] oct-2-ylidenemethylene bis (p-phenyleneoxyethylene) ]dipyrrolidine dihydrochloride exhibit oral antifertility activity in rats when administered in dosages of 5 mg./kg.

The compounds of Formulae I, II and III also exhibit activity as estrogens and estrogen antagonists. For example, the compound 4,4-(spiro[3.5]non-2-ylidenemethylene)diphenol is both uterotropic and estrogenic in the immature, ovariectomized female rate.

In addition, the compounds of Formulae I, II and III exhibit central nervous system activity. Illustratively, the compounds 4,4'- (spiro[3 .5] non-Z-ylidenemethylene) diphenol diacetate,

a-[p-(dimethylamino)phenyl] -a-spiro [3 .5] non-2-ylidenep-cresol,

4,4-'- (s piro [3 .4] Oct-Z-ylidenemethylene) diphenol, and

1- [2-[ [ix-(p-rnethoxyphenyl)ot-spir0 [3 .5] non-Z-ylideneot-tolyl] oxy] ethyl] pyrrolidine hydrochloride function as stimulants when administered intraperitoneally to rats in dosages of 30 mg./ kg. and the compound 4,4- [spiro[cyclobutane-1,2'-norbornan]-3 ylidenemethylene] diphenol hemihydrate functions as a nicotine antagonist when administered intraperitoneally to rats in a dosage of 200 mg./kg.

The tertiary carbinols (XIV and XV) exhibit pharmacological activity in addition to being useful as starting materials for preparing compounds Ib, IIb and III respectively. For example, a-(p-hydroxyphenyl)-a-spiro[3.5] non-Z-ylidene-4-pyridinemethanol, when administered intraperitoneally to rats in a dosage of 200 mg./ kg. functions as a nicotine antagonist.

For purposes of administration to animals, including mammals, the novel compounds of the invention can be combined with solid or liquid pharmaceutical carriers and formulated in the form of tablets, powder packets, capsules and like solid dosage forms, using starch and like excipients, or dissolved or suspended in suitable solvents or vehicles, for oral or parenteral administration.

The following examples are set forth to illustrate my invention and to enable persons skilled in the art to better understand and practice the invention and are not intended to limit the same.

EXAMPLE 1 4 ,4 (spiro [3.5 ]n0n-2-ylidenemethylene) diphenol A solution of 5.51 g. of methyl spiro[3.5]nonane-2-carboxylate in 60 ml. of tetrahydrofuran is added to a solution of the Grignard reagent prepared from 17.0 g. of p-(Z-tetrahydropyranyloxy)bromobenzene and 1.62 g. of magnesium in 200 ml. of tetrahydrofuran. Following 16 hours standing at room temperature, ml. of saturated aqueous ammonium chloride is added. The organic layer is separated, washed with water and a saturated solution of sodium chloride and taken to dryness. A solution of the residual oil in ml. of methanol is treated with 40 ml. of 2.5 N hydrochloric acid and stirred at room temperature for 2.5 hours. The bulk of the solvent is removed in vacuum and the residue taken up in ether. The organic layer is washed with water and aqueous sodium bicarbonate and then extracted with five SO-ml. portions of aqueous sodium hydroxide. The basic extract is acidified and the precipitated oil taken up in ether, and this last solution is washed with water and a saturated solution of sodium chloride and then taken to dryness. The residual solid is then recrystallized twice from aqueous methanol to give 4.49 g. of 4,4-(spiro [3 .5] non-2-ylidenemthylene) diphenol, melting point 203204.5 C.

Analysis.Calcd. for C H O (percent): C, 82.46; H, 7.55. Found( percent): C, 83.09; H, 7.83.

EXAMPLE 2 4,4- (spiro [3.5] non-Z-ylidenemethylene diphenol d iacetate A solution of 2.0 g. of 4,4-(spiro[3.5]non-2-ylidenemethylene)dipheno1 (Example 1) in 30 ml. of acetic anhydride is stirred for 4 hours at reflux and 17 hours at room temperature. The solution is taken to dryness and the residue crystallized twice from Skellysolve B hexanes to yield 1.63 g. of 4,4'-(spiro[3.5]non-2-ylidenemethylene) diphenol diacetate, melting point 119-121 C.

Analysis.Calcd. for C H O (percent): C, 77.20; H, 6.98. Found (percent): C, 77.20; H, 7.11.

EXAMPLE 3 1,1 [spiro[3.5]nOn-Z-yZidenemeflzylenebis(p-pherzyleneonethylene)]dipyrrolidine and dihydrochloride thereof Sodium hydride (0.85 g., 56% in mineral oil) is added to a solution of 3.2. g. of 4,4-(spiro[3.5]non-2-ylidenemethylene)diphenol (Example 1) in 35 ml. of dimethylformamide and 105 ml. of benzene. Following 20 minutes stirring there is added 5.35 g. of a 1:1 mixture of N-(B- chloroethyl)pyrrolidine and toluene. The solution is heated at reflux overnight, cooled and washed in turn with Water,

1 N sodium hydroxide, water and a saturated solution of sodium chloride. The residue which remains when the solution is taken to dryness is dissolved in ether. Hydrogen chloride is passed through the ethereal solution and the precipitated solid collected on a filter. The solid is recrystallized twice from ethanol to give 4.97 g. of 1,1- [spiro[3.5]non 2 ylidenemethylenebis(p-phenyleneoxyethylene)]dipyrrolidine dihydrochloride, melting point 281-2835 C.

Analysis.-Calcd. for C H N O Cl (percent): C, 69.49; H, 8.23. Found (percent): C, 69.18; H, 8.36.

To a mixture of ether and aqueous sodium bicarbonate there is added 1,1'-[spiro[3.5]non-2-ylidenemethylenebis (p-phenyleneoxyethylene) dipyrrolidine dihydrochloride. The organic layer is separated from the mixture, washed with water and a saturated solution of sodium chloride and taken to dryness to yield 1,1-[spiro[3.5]non-2-ylidenemethylenebis (p-phenyleneoxyethylene) 1 dipyrrolidine.

EXAMPLE 4 4,4-( spiro [3 .5 non-Z-ylidenemethylene) dianisol (3.) a.- (DI (p-ANISYL) SPIRO [3.5] NGNANE-2-METHANOL To a solution of the Grignard reagent prepared from 14.9 g. of p-bromoanisole and 1.95 g. of magnesium in 150 ml. of tetrahydrofuran there is added 3.72 g. of methyl spiro[3.5]nonane-2-carboxylate in 50 ml. of tetrahydrofuran. The mixture is allowed to stand for 18 hours at room temperature, cooled in ice and treated with 50 ml. of saturated aqueous ammonium chloride. The organic layer is separated, washed with water and a saturated solution of sodium chloride, and evaporated to dryness. The residue is treated with Skellysolve B hexanes and the solid that precipitates is collected and washed again with Skellysolve B hexanes. The solid is chromatographed over magnesium silicate (Florisil) (elution with 5% acetone-95% Skellysolve B hexanes by volume). Fractions melting over 98 C. are combined and recrystallized twice from Skellysolve B hexanes to yield 5.08 g. of a,a-di(p-ar1isyl)spiro[3.5]no nane-Z-methanol, melting point 112-1135 C.

Analysis.--Calcd. for C H 0 (percent): C, 78.68; H, 8.25. Found (percent): C, 78.30; H, 8.21.

(13) 4,4' SPIRO [3.5 ]NON2YLIDENEME THYLENE) DIANISOLE A mixture of 3.10 g. of a,u-di(p-anisyl)spiro[3.5] nonane-Z-methanol and 200 mg. of p-toluenesulfonic acid in 200 ml. of benzene is refluxed under a Dean-Stark trap for 2 hours. The solution is allowed to cool, washed with aqueous sodium bicarbonate and a saturated solution of sodium chloride and taken to dryness. The residual solid is recrystallized from petroleum ether to yield 2.60 g. of 4,4'-(spiro{3.5]non-2-ylidenemethylene)dianisole in the form of crystals, melting point 8284 C.

Analysis.Calcd. for C H O (percent): C, 82.72; H, 8.10. Found (percent): C, 82.67; H, 8.32.

8 EXAMPLE 5 vt-Phenyl-a-spz'ro [3 -5 non-Z-y lidene-p-cresol (a) a.- (p-HYDROXYPHENYL) -a-PHENYLSPIRO 3. 5] NONANE-Z-METHANOL A solution of 4.13 g. of 2-benzoylspiro[3.5]nonane in 50 ml. of tetrahydrofuran is added to the Grignard reagent prepared from 5.14 g. of p-(Z-tetrahydropyranyloxy)bromobenzene and 0.5 g. of magnesium in 50 ml. of tetrahydrofuran. This mixture is allowed to stand at room temperature for 17 hours and then 50 ml. of saturated ammonium chloride is added. The organic layer is washed with water and a saturated solution of sodium chloride and taken to dryness. The residue is dissolved in ml. of methanol, 25 ml. of 2.5 N hydrochloric acid is added and the mixture stirred for 3 hours at room temperature. The bulk of the solvent is removed in vacuo and ether added to the residue. The organic layer is washed with Water and a saturated solution of sodium chloride and taken to dryness to afford a-(p-hydroxyphenyl)a-phenylspiro{3.51nonane-2-methanol as a waxy solid.

(b) a-PHENYLa-SPIROtSb]NON-ZYLIDENE-P-CRESOL A solution of 3.36 g. a-(p-hydroxyphenyl)-a-phenylspiro[3.51nonane-2-methanol and 0.30 g. of p-toluenesulfonic acid in 250 ml. of benzene, is heated at reflux for 5 hours and then allowed to cool. The solution is then washed with water and a saturated solution of sodium chloride and taken to dryness. The residue is chromatographed on 250 ml. of silica gel (elution with methylene chloride). The fractions which are similar by thin layer chromatography are combined and recrystallized once from petroleum ether and twice from Skellysolve B hexanes to yield 1.40 g. of a-phenyl-a-spiro[3.5]non-2- ylidene-p-cresol, melting point 111-115 C.

Analysis.Calcd. for 0 11 0 (percent): C, 86.80; H, 7.95. Found (percent): C, 86.35; H, 7.87.

EXAMPLE 6 a- (p-Fluorophenyl -a-sp-iro [3.5] n0n-2ylidene-p-cres0l (a) a- (p-FLUOROPHENYL) -a- -HYDROXYPHENYL) SPIRO[3.51'NONANE-2-METHANOL A solution of 3.50 g. of 2- [p-(Z-tetrahydropropyrranyloxy)benzoyl}spiro[3.5]nonane in 50 m1. of tetrahydrofuran is added to the Grignard reagent prepared from 2.50 g. of 4-fluorobromobenzene and 0.35 g. of magnesium in 50 ml. of tetrahydrofuran. This mixture is allowed to stand at room temperature overnight and then 60 ml. of saturated aqueous ammonium chloride is added. The organic layer is washed with water and a saturated solution of sodium chloride and taken to dryness. The residue is dissolved in 100 ml. of methanol, 25 ml. of 2.5 N hydrochloric acid is added and the mixture is stirred for 2 hours at room temperature. The bulk of the solvent is removed in vacuo and ether added to the residue. The organic layer is washed with water and a saturated solution of sodium chloride and taken to dryness to yield a-(p-fluorophenyD- nc- (p-hydroxyphenyl) spiro 3.5 nonane-Z-methanol.

(b) a (p-FLUOROPHENYL)-e-SPIRO[3.5]NON Q-YLIDENE- -ORESOL A solution of 3.46 g. of e-(p-fluorophenyl)-u-(p-hydroxyphenyDspiro[3.51nonane-2-methanol and 0.30 g. of p-toluenesulfonic acid in 120 ml. of benzene is heated at reflux for 3 hours, and then allowed to stand at room temperature. The solution is then washed with water and an aqueous solution of sodium bicarbonate and taken to dryness. The residue is chromatographed on 400 ml. of Florisil (elution with 5% acetone-95% Skellysolve B hexanes, by volume). The fractions which are similar by thin layer chromatography are combined and recrystallized three times from Skellysolve B hexanes to yield 0.92 g. of 06- (p-fluorophenyl -u-spiro [3.5 non-2-y1idene-p-cresol, melting point -1175 C.

Analysis.Calcd. for C H FO (percent): C, 81.95; H, 7.19. Found (percent): C. 82.04; H, 7.26.

EXAMPLE 7 a-Spiro[3.5]nOn-Z-yIidene-a-(p-lolyl)-p-cresol (a) a.( p-HYDROXYPHIGNYL) -o. (p-Tt )LYL) SPIRO[3.5]NONANE-ZMETHANOL A solution of 4.0 g. of 2-[p-(Z-tetrahydropyranyloxy)- benzoyl]spiro[3.5]nonane in 50 ml. of tetrahydrofuran is added to the Grignard reagent prepared from 2.30 g. of 4-bromo-toluene and 0.31 g. of magnesium in 50 ml. of tetrahydrofuran. This mixture is allowed to stand at room temperature for 17 hours and then 50 ml. of saturated aqueous ammonium chloride is added. The organic layer is washed with water and a saturated solution of sodium chloride and taken to dryness. The residue is dissolved in 200 ml. of methanol, 50 ml. of 2.5 N hydrochloric acid is added and the mixture stirred for 2 hours at room temperature. The bulk of the methanol is removed in vacuo and ether added to the residue. The organic layer is washed with water and a saturated solution of sodium chloride and taken to dryness to yield a-(p-hydroxyphenyl) -u- (p-tolyl) spiro [3 .5 nonane-Z-methanol.

(b) a-SPIRO[3.5]NON-2-YLIDENE-a-(p-TOLYL)p-CRESOL A solution of 4.45 g. a-(phydroxyphenyl)-a-(p-tolyl) spiro[3.5]nonane-2-methanol and 0.4 g. of p-toluenesulfonic acid in 200 ml. of benzene is heated at reflux for 5 hours. The solution is then washed with water and an aqueous solution of sodium bicarbonate and taken to dryness. The residue is recrystallized three times from Skellysolve B hexanes to yield 2.10 g. of u-spiro[3.5]non- 2-ylidene-a-(p-tolyl)-p-cresol, melting point 116119 C.

Analysis.Calcd. for C H O (percent): C, 86.74; H, 8.23. Found (percent): C, 86.19; H, 8.50.

EXAMPLE 8 ocp-M ethoxyphenyl -u-spir0 [3 .5 no'n-Z-ylz'dene-pcresol (a) a (p-HYDROXYPHENYL-a ('p-METHOXYPHENY L) A solution of 9.99 g. of 2-(p-methoxybenzoyl)spiro- [3.5]nonane in 100 ml. of tetrahydrofuran is added to the Grignard reagent prepared from 11.0 g. of p-(2-tetrahydropyranyloxy)-bromobenzene and 1.04 g. of magnesium in 120 ml. of tetrahydrofuran. After allowing the solution to stand overnight at room temperature, 100 ml. of saturated aqueous ammonium chloride is added. The organic layer is washed with water and a saturated solution of sodium chloride and taken to dryness. The residue is dissolved in 250 ml. of methanol, 25 ml. of 2.5 N hydrochloric acid is added and the mixture stirred for 3 hours at room temperature. The bulk of the solvent is removed in vacuo and a mixture of benzene and ether are added to the residue. The organic layer is washed with water and a saturated solution of sodium chloride and taken to dryness to yield a-(p-hydroxyphenyl)-a-(p-methoxyphenyl) spiro [3 .5 1 nonane-2-methanol.

(b) u.-(p-METHOXYPHENYL)-aSPIRO[3.5] NON-.Z-YLIDENE-p-CRESOL A solution of 17.55 g. of a-(p-hydroxyphenyl)-a-(pmethoxyphenyl)spiro[3.5]nonane-2-methanol and 1.0 g. of p-toluenesulfonic acid in 250 ml. of benzene is heated at reflux for 4 hours and then allowed to stand at room temperature. The solution is then washed with water and a saturated solution of sodium chloride and taken to dryness. The residue, a black gum, is chromatographed on 1 liter of silica gel (elution with methylene chloride). The fractions which are similar by thin layer chromatography are combined and chromatographed on Florisil (elution with 2% acetone98% Skellysolve B hexanes, by volume). The fractions which are similar by thin layer chromatography are combined and recrystallized from cyclohexane and then from Skellysolve B hexanes to yield a-(p methoxyphenyD-a-spiro[3.5]non-2-ylidene-pcresol of melting point 9798 C.

Analysis.-Calcd. for C C O (percent): C, 82.59; H, 7.84. Found (percent): C, 81.75; H, 7.63.

1O EXAMPLE 9 1 l2 l |tx-(p-nzethoxyplzellyl)-a-spiro[3,5 [non-Z-ylhlenep-t0lyl]0xy]ethyl]pyrrolidine and hydrochloride thereof A solution of 4.0 g. of 2-(p-methoxybenzoyl)spiro- [3.5]nonane in 50 ml. of tetrahydrofuran is added to the Grignard reagent prepared from 4.18 g. of p-(2-pyrrolidinoethoxy)bromobenzene and 0.38 g. of magnesium in 50 ml. of tetrahydrofuran. This mixture is allowed to stand at room temperature overnight and then 10 ml. of water added. The organic layer is decanted from the gel and the gel suspended in water and ether. The ether and organic layers are combined and taken to dryness. The residue is taken up in ether and extracted with three 50-ml. portions of 2.5 N hydrochloric acid. The acid extract is made basic, taken up in ether, washed with water and a saturated solution of sodium chloride and taken to dryness to yield 2.98 g. of crude product. This product is chromatographed on 400 ml. of silica gel (eluted with 2 l. of 1:1 solution of methylene chloride and Skellysolve B hexanes saturated with ammonia). Fractions similar by thin layer chromatography are combined, washed with ml. of 2.5 N hydrochloric acid and then taken to dryness. The residue is recrystallized twice from acetonitrile to yield 1.37 g. of 1-[2-[[(pmethoxyphenyl) 0c spiro[3.5]non-2-ylidene-p-tolyl]- oxy]ethyl]pyrrolidine hydrochloride, melting point 203- 205 C.

Analysis.Calcd. for C H ClNO (percent): 74.41; H, 8.18. Found (percent): C, 73.67; H, 8.18.

To a mixture of ether and aqueous sodium bicarbonate there is added 1[2-[[(P-methoxyphenyl)-a-spiro- [3 .5] non-2-ylidene-p-tolyl] oxy] ethyl]pyrrolidine hydrochloride. The organic layer is separated from the mixture, washed with water and a saturated solution of sodium chloride and taken to dryness to yield 1-[2-[ (p-methoxyphenyl) a spiro[3.5]non-Z-ylidene-p-tolyl]oxy]ethyl] pyrrolidine.

EXAMPLE 10 a [p- [2- (l-pyrrolidinyl) ethoxy phenyl] -a-spir0 [3.5]non-Z-ylidene-p-cresol A solution of 4.97 g. of 2-[p-(2-tetrahydropyranyloxy)- benzoyl]spiro[3.5]nonane in ml. of tetrahydrofuran is added to the Grignard reagent prepared from 4.12 g. of

' p-(Z-pyrrolidinoethoxy)bromobenzene and 3.70 g. of

magnesium in 50 ml. of tetrahydrofuran. This mixture is allowed to stand at room temperature overnight and 2 ml. of water is added. The organic layer is decanted from the gel and the gel suspended in Water and ether. The ether and organic layers are combined, washed with water and a saturated solution of sodium chloride and taken to dryness. The residue is taken up in a mixture consisting of ml. of methanol and 100 m1. of 2.5 N hydrochloric acid and stirred at room temperature for two hours. The methanol is removed in vacuo and the precipitate taken up in methylene chloride. This solution is taken to dryness and the resulting amorphous foam is suspended in a solution of 0.3 N sodium hydroxide. The solid formed in this suspension is taken up in ether and the ether solution treated with carbon dioxide gas. The solid that precipitates is suspended in aqueous methanol and the mixture acidified with carbon dioxide and then taken to dryness. The residue is taken up in chloroform and then taken to dryness. The residue is recrystallized twice from methylene chloride: methanol to yield 2.21 g. of a-[p-[Z (1 pyrrolidinyl)ethoxy]phenyl]-tx-spiro- [3.5]non-2ylidene-p-cresol, melting point l87 C.

AnaIysis.Calcd. for C H NO (percent): C, 80.53; H, 8.46. Found (percent): C, 80.01; H, 7.99.

EXAMPLE 11 a-[p-(Dimethylal'nino)phenyl]oc-spiro [3.5111011-2- ylidene-p-cresol and hydrochloride thereof A solution of 4.0 g. of 2-[p-(2-tetrahydropyranyloxy)- benzoyl]spiro[3.5]nonane in 50 ml. of tetrahydrofuran is 11 added to the Grignard reagent prepared from 2.56 g. of p-(dimethylamino)bromobenzene and 0.31 g. of magnesium in 50 ml. of tetrahydrofuran. The mixture is allowed to stand at room temperature overnight and 2 ml. of water is added dropwise. The organic layer is separated from the precipitated gel, washed with water and a saturated solution of sodium chloride and taken to dryness. The residue is taken up in a mixture of 100 ml. of methanol and 100 ml. of 2.5 N hydrochloric acid and stirred at room temperature for 3 hours. The bulk of the methanol is removed in vacuo. The residual mixture is extracted with methylene chloride and the extract taken to dryness. The residual solid is washed with ether and recrystallized twice from a solution of methanol and 2.5 N hydrochloric acid to yield 1.96 g. of u-[p- (dimethylamino)phenyl]-a-spiro[3,5]non 2 ylidene-pcresol hydrochloride, melting point 235241 C. (dec.).

Analysis.Calcd. for C H ClN (percent): C, 75.07; H, 7.88. Found (percent): C, 75.53; H, 7.99.

To a mixture of ether and aqueous sodium bicarbonate there is added ot-[p-(dimethylamino)phenyl1-a-spiro[3.5] non-2-ylidene-p-cresol hydrochloride. The organic layer is separated from the mixture, washed with Water and a saturated solution of sodium chloride and taken to dryness to yield a-[p-(dimethylamino)phenyl]-a-spiro[3.5] non-2-ylidei1e-p-cresol, melting point 15 5-157 C.

Analysis.-Calcd. for C H NO (percent): C, 82.95 H, 8.41. Found (percent): C, 82.93; H, 8.79.

EXAMPLE 12 04- (p-Melhoxyplzenyl) -a-spiro[3.5 n0n-2-yl- 4-pyridinemethanol To a solution of 7.5 ml. of 1.6 N butyl lithium in pentane and an equal volume of ether in a solid carbon dioxide-acetone bath, there is added over a period of about 1 hour a solution of 2.0 g. of 4-bromopyridiue in 60 ml. of ether. Following 15 minutes stirring, a solution of 2.92 g. of Z-(p-methoxybenzoyl)spiro[3.5]n0nane in ml. of ether is added over 1 hour. The mixture is stirred in the above cold bath for an additional 90 minutes and in an ice bath for 1 hour. Saturated aqueous ammonium chloride is then added and the organic layer is separated. The organic layer is extracted several times with 2.5 N hydrochloric acid and the acid extracts are made basic. The precipitate is collected and recrystallized twice from aqueous methanol to afford 2.07 g. of oc- (p-methoxyphenyl)-a-spiro[3.5]non-2-yl 4 pyridinemethanol, melting point 194l97 C.

Analysis.Calcd. for C H NO (percent): C, 78.30; H, 8.07. Found (percent): C, 77.60; H, 7.98.

EXAMPLE 13 06- (p-Hydroxyphenyl -a-spiro[3.5 non-Z-yl- 4 -pyridinemethanol To a solution of 9.8 ml. of 1.6 N butyl lithium in pentane and an equal volume of ether in a solid carbon dioxide-acetone bath, there is added over a period of 30 minutes a solution of 2.61 g. of 4bromopyridine in 68 ml. of ether. Following 15 minutes stirring, a solution of 5.0 g. of 2-[p-(2 tetrahydropyranyloxy)benzoyl]spiro [3.5]nonane in ml. of ether is added. The mixture is stirred in the above cold bath for an additional minutes and in an ice bath for 1 hour. Saturated aqueous ammonium chloride is added and the organic layer is separated. The organic layer is washed with water and then extracted with four 50-ml. portions of 2.5 N hydrochloric acid. The acid solutions are combined, made basic with sodium bicarbonate and extracted with hot chloroform. The material that does not dissolve in the chloroform is separated from the mixture and then combined with the residue remaining after the chloroform solution is taken to dryness. This combined crude product is then recrystallized twice from aqueous methanol to yield 1.02 g. of a-(p-hydroxyphenyl)-or-spiro[3.5]non-2-yl 4 pyridinemethanol, melting point 233235 C.

12. Analysis.-Calcd. for C H NO (percent): C, 77.98; H, 7.79. Found (percent) C, 77.07; H, 7.80.

EXAMPLE 14 4,4'-(spiro [3.4]0ct-2-ylidenemethylene)diphenol and hemihydrare thereof To a cold solution of the Grignard reagent from 23.2 g. of p(2-tetrahydropyranyloxy)bromobenzene and 2.20 g. of magnesium in 200 ml. of tetrahydrofuran, there is added 7.50 g. of methyl spiro[3.4]octane-2-carboxylate in ml. of tetrahydrofuran. The mixture is allowed to stand overnight at room temperature, cooled in ice and treated with ml. of saturated aqueous ammonium chloride. The organic layer is separated, Washed with Water and brine and taken to dryness. The residual oil is dissolved in 250 m1. of methanol; 50 ml. of 2.5 N hydrochloric acid is added and the mixture allowed to stand at room temperature for 3 hours. The bulk of the solvent is removed in vacuo, and the mixture diluted with ether. The organic layer is washed with water and then extracted with three 50-ml. portions of 1 N sodium hydroxide. The solid, which is obtained when these basic extracts are acidified with solid carbon dioxide is collected on a filter. This product is recrystallized in turn from benzene and aqueous methanol to give 8.15 g. of 4,4-(spiro[3.4] oct 2 ylidenemethylene)diphenol hemihydrate, melting point 185187.5 C.

Analysis.Calcd. for c n o /zmo (percent): C, 79.96; H, 7.35. Found (percent): C, 79.21; H, 6.91.

The hemihydrate is maintained for 48 hours at about C. and about 1 mm. of mercury pressure to obtain 4,4'(spiro [3 .4] oct-2-ylidenemethylene diphenol.

EXAMPLE 15 4,4 (.rpz'r0[3 .4 oct-Z-ylidenemetkylerze) diphenol diacetate A mixture of 2.0 g. of 4,4'-(spiro[3.4]oct-2-ylidenemethylene)diphenol (Example 14) in 30 ml. of acetic anhydride is heated at reflux for 3 hours. The solution is taken to dryness under high vacuum and the residue recrystallized twice from Skellysolve B hexanes to yield 0.85 g. of 4,4-(spiro[3.4]oct-2-ylidenemethylene)diphenol diacetate, melting point 73.5-75 C.

Analysis.-Calcd. for C H O (percent): C, 76.90; H, 6.71. Found (percent): C, 76.73; H, 6.63.

EXAMPLE l6 1,1-[(spiro[3.4]0ct 2 ylidenemethylene)bis-(p phenyleneoxyethylene)1dipyrrolidine and dihydrochloride thereof A solution of 3.06 g. of 4,4'-(spiro[3.4]oct-2-ylidenemethylene)diphenol (Example 14) in 35 ml. of dimethylformamide and 105 ml. of benzene is treated with 0.85 g. of 56% sodium hydride in mineral oil. Following 30 minutes stirring, 5.38 g. of a 1:1 mixture of N-(fl-chloroethyl)pyrrolidine and toluene is added, and the solution is heated at reflux overnight and then allowed to cool. The resulting mixture is washed in turn with Water, 1 N sodium hydroxide, water, and a saturated solution of sodium chloride and then taken to dryness. The residue is dissolved in ether and treated with hydrogen chloride. The precipitated solid is recrystallized twice from methanol2ethyl acetate to yield 3.54 g. of 1,1'-[(spiro[3.4]oct- 2 ylidenemethylene)bis-(p phenyleneoxyethylene)1dipyrrolidine dihydrochioride, melting point 270-272 C.

A naZysis.-Calcd. for C H N O Cl (percent): C, 69.09; H, 8.08; N, 12.36. Found (percent): C, 69.72; H, 8.19; N, 12.40.

To a mixture of ether and aqueous sodium bicarbonate there is added 1,1-[(spiro[3.4]oct-2-ylidenemethylene) bis(p-phenyleneoxyethylene) dipyrrolidine dihydrochloride. The organic layer is separated from the mixture, washed with water and a saturated solution of sodium chloride and taken to dryness to yield l,l'-[('spiro[3.4]

13 oct 2 ylidenemethylene)bis(p-phenyleneoxyethylene)] dipyrrolidine.

EXAMPLE 17 3-[ [a- (p-methoxyphenyl) -a-spirl[3.5]non-Z-ylidenep-t0lyl10xy]-1,2-pr0panedi0l and hemihydrate thereof To a solution of 1.35 g. of 4,4'-(spiro[3.5]non-2-ylidenernethylene)diphenol (Example 1) in 40 ml. of methanol and 1 ml. of 4.35 N methanolic sodium methoxide there is added 0.50 g. of 1 chloro-2,3-propanediol. The solution is heated at reflux, allowed to cool and then diluted with water. The resulting mixture is extracted With ether:benzene and the organic layer separated. The organic layer is Washed with water, a saturated solution of sodium chloride and then taken to dryness. The residue is chromatographed on Florisil (elution with acetone- 95% Skellysolve B hexanes and then with acetone- 80% Skellysolve B hexanes). Fractions which are similar by thin layer chromatography are combined and recrystallized from cyclohexane to yield 0.72 g. of 3[[a- (p-methoxyphenyl)-a-spiro[3.5]non -2 ylidene-p-tolyl] oxy]-1,2-propanediol hemihydrate, melting point 52- 57 C.

Analysis.Calcd. for C H O /2H O (percent): C, 74.79; H, 7.97. Found (percent): C, 75.10; H, 8.34.

The hemihydrate is maintained for 48 hours at about 50 C. and about 1 mm. of mercury pressure to obtain 3-[ [a-(p-methoxyphenyl)-a-spiro[3.5]non-2 ylidene ptolyl] oxy] -1,2-propanediol.

EXAMPLE l8 u-(4-pyridyl) -a-spiro [3.5] n0lz-2-ylidene-p-cresol A solution of 3.70 g. of u-(p-hydroxyphenyl)-a-spiro [3.5]non-2-yl-4-pyridinemethanol and 1.0 g. of p-toluenesulfonic acid in 100 ml. of ethanol is heated at reflux for 5 hours and then the ethanol is removed in vacuo. The residue is taken up in methylene chloride, washed with aqueous sodium bicarbonate and then taken to dryness. The residue is an amorphous foam which crystallizes on scratching. The solid is recrystallized twice from aqueous methanol to yield 1.95 g. of a.-(4-pyridyl)-u-spiro[3.5] non-2-ylidene-p-cresol, melting point 206-2075 C.

Analysis.Calcd. for C H NO (percent): C, 82.58; H, 7.59. Found (percent): C, 81.93; H, 7.69.

EXAMPLE 19 p-(u-Spiro [3.5]n0n-2-ylstyryl)anis0le To a solution of 4.70 g. of the ylide,

and 6.8 ml. of 1.6 N butyl lithium in 60 ml. of tetrahydrofuran is added a solution of 2.7 g. of Z-(p-methoxybenzoyl)spiro[3.5]nonane in ml. of tetrahydrofuran. This mixture is stirred at room temperature, brought to reflux, and then cooled and stirred at room temperature overnight. After adding water, the organic layer is separated from the mixture, washed with water and then a saturated solution of sodium chloride. The organic layer is taken to dryness and the residue, which is in the form of a gum, is chromatographed on silica gel (eluted with methylene chloride). Fractions which are similar by thin layer chromatography are combined and recrystallized several times from petroleum ether to yield 0.46 g. of p-(wspiro[3.5]non-2-ylstyryl)anisole, melting point 67- 71 C.

Analysis.Calcd. for C H O (percent): C, 86.70; H, 8.49. Found (percent): C, 87.47; H, 8.78.

EXAMPLE 2O 4,4'-[spiro [cyclobutane-I ,2-n0rb0rnan] -3-ylidenemetlzylene]diplzen0l and hemihydrate thereof To a solution of 4.14 g. of methyl spiro[cyclobutane- 1,2'-norbornau]-3-carboxylate in 50 ml. of tetrahydrofuran, there is added the Grignard reagent prepared from 11.5 g. of p-(Z-tetrahydropyranyloxy)bromobenzene and 1.10 g. of magnesium in ml. of tetrahydrofuran. Following 18 hours standing at room temperature the mixture is cooled in ice and treated with 60 ml. of saturated aqueous ammonium chloride. The organic layer is diluted with benzene, washed with Water, a saturated solution of sodium chloride and taken to dryness. A mixture of the residue in 200 ml. of methanol and 50 ml. of 2.5 N hydro chloric acid is stirred at room temperature for 3 hours and the bulk of the solvent removed in vacuo. The residue is collected on a filter, dried and recrystallized from ether:Skellysolve B hexanes to give 5.80 g. of the crude product, melting point 178182 C. The crude product is recrystallized from aqueous methanol to yield 3.80 g. of 4,4-'- spiro [cyclobutane- 1 ,2-norbornan] -3-ylidenemethylene]diphenol hemihydrate, melting point 182.5187 C.

Analysis.-Calcd. for C H O /2H O (percent): C, 80.90; H, 7.38. Found (percent): C, 80.55; H, 7.37.

The hemihydrate is maintained for 48 hours at about C. and about 1 mm. of mercury to obtain 4,4'-[spiro [cyclobutane 1,2 norbornan] 3 ylidenemethylene] diphenol.

EXAMPLE 21 4 ,4 spiro [cyclobutane-I ,2'-n0rb0rnan -3-yl id enemethylene1diphen0l diacetate A solution of 2.0 g. of 4,4-[spiro[cyc10butane-1,2- norbornan] 3 ylidenemethylene]diphenol hemihydrate (Example 20) in 30 ml. of acetic anhydride is heated at reflux for 4 hours. The solvent is removed in vacuo and the residual solid recrystallized twice from Skellysolve B hexanes to yield 1.20 g. of 4,4-[spiro[cyclobutane-1,2'- norbornan]-3-ylidenemethylene]diphenol diacetate, melting point 7072 C.

Analysis.-Calcd. for C H O (percent): C, 77.86; H, 6.78. Found (percent): C, 78.30; H, 7.40.

I claim:

1. A compound of the formula:

References Cited UNITED STATES PATENTS 2,571,954 10/1951 Shelton et a1 260619 A 3,237,200 2/1966 Barany et a1 260619 A 3,287,397 11/1966 Olsson et a1. 260619 A FOREIGN PATENTS 602,269 5/1948 Great Britain 2'60619 A BERNARD HELFIN, Primary Examiner US. Cl. X.R.

260-649 R, 619 D, 619 F, 612 R, 613 R, 479 R, 576, 571, 567.6 R, 326.5 N, 290 R, 297 R, 326.81, 326.5 R, 268 R, 999

UNITED STATES PATENT OFFICE CERTIFICATE OF CGRRECTION Pa e 3, 5 Dated January 18, 1972 Inventor(s) Dan i e l Lednl cer It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 40, before Formula VI should read B) Column 4, l ine 25, for "and read or f T 'l Column 5, l ine 28, for 2heptenyl read 2-heptenyl Column 6. line 7, for "rate" read rat l ine 65, For "yl idenemthylene" read yl idenemethylene Column 7, line 41, for "Li-(Cl (pread c1,cx-Dl (p- Column 8, line 2, for "[5-51 read [5.5]

l ines 45- l l, for "tetrahydropropyrranyloxy" read tetrahydropyrranyloxy Column 9, l ine 57, For "(p-hydroxyphenyl-or- (pmethoxyphenyl read (p-hydroxyphenyl )OL' (p-methoxyphenyl )spi ro- [5.51-nonane-2-methanol Column 10, line 41, for "ol[p" read d-[p- Column 11, line 16, for "[5,5]" read [5.5]

Signed and sealed this 1st day of August 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOITSCHALK Attesting Officer Commissioner of Patents FORM PO-105O (10-69) USCOMM-DC 6O376-P69 LLS. GOVERNMENT PRINTING OFFICE: I959 O-365-334 

